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Mechanisms of Disease: mechanism-based classification of neuropathic pain—a critical analysis

Abstract

Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological mechanisms. Application of this approach in the clinic is problematic, however, owing to a lack of precise tools to assess symptoms and signs, and difficulties in correlating symptoms and signs with mechanisms. Development and validation of diagnostic methods to identify mechanisms, together with pharmacological agents that specifically target these mechanisms, seems to be the most logical and rational way of improving neuropathic pain treatment.

Key Points

  • Classification of neuropathic pain on the basis of disease or location has considerable shortcomings, and an approach based on disease mechanisms might provide a viable alternative

  • To develop an effective mechanism-based classification, we need to be able to relate symptoms and signs to mechanisms, and to identify specific treatments for specific mechanisms

  • One mechanism might give rise to different symptoms and signs; for example, upregulation of sodium channels in C-fibers increases fiber activity, resulting in burning pain, paroxysms and dynamic mechanical allodynia

  • Similarly, one symptom or sign can be caused by several initiating mechanisms; for example, cold allodynia can be attributed to different mechanisms in peripheral and central neuropathic pain

  • It is becoming clear that we have not yet obtained a viable mechanism-based classification for neuropathic pain, and more-rigorous studies are required to test this approach

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Figure 1: Cascade of events following peripheral and central nervous system lesion resulting in central sensitization.

References

  1. McQuay and Moore (1998) An evidence based resource for pain relief. Oxford: Oxford University Press

    Google Scholar 

  2. Finnerup NB et al. (2005) Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118: 289–305

    CAS  PubMed  Article  Google Scholar 

  3. Baron R (2006) Mechanisms of Disease: neuropathic pain—a clinical perspective. Nat Clin Pract Neurol 2: 95–106

    PubMed  Article  Google Scholar 

  4. Jensen TS and Baron R (2003) Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102: 1–8

    PubMed  Article  Google Scholar 

  5. Farrar JT et al. (2001) Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94: 149–158

    CAS  PubMed  Article  Google Scholar 

  6. Rasmussen PV et al. (2004) Symptoms and signs in patients with suspected neuropathic pain. Pain 110: 461–469

    PubMed  Article  Google Scholar 

  7. Bouhassira D et al. (2005) Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114: 29–36

    PubMed  Article  Google Scholar 

  8. Bennett M (2001) The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 92: 147–157

    CAS  PubMed  Article  Google Scholar 

  9. Krause SJ and Backonja M (2003) Development of a neuropathic pain questionnaire. Clin J Pain 19: 306–314

    PubMed  Article  Google Scholar 

  10. Perkins FM et al. (2004) Development and validation of a brief, descriptive Danish pain questionnaire (BDDPQ). Acta Anaesthesiol Scand 48: 486–490

    CAS  PubMed  Article  Google Scholar 

  11. Rasmussen PV et al. (2004) Therapeutic outcome in neuropathic pain: relationship to evidence of nervous system lesion. Eur J Neurol 11: 545–553

    CAS  PubMed  Article  Google Scholar 

  12. Besson JM (1999) The neurobiology of pain. Lancet 353: 1610–1615

    CAS  PubMed  Article  Google Scholar 

  13. Julius D and Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413: 203–210

    CAS  PubMed  Article  Google Scholar 

  14. Watkins LR et al. (2001) Spinal cord glia: new players in pain. Pain 93: 201–205

    CAS  PubMed  Article  Google Scholar 

  15. Mantyh PW et al. (2002) Molecular mechanisms of cancer pain. Nat Rev Cancer 2: 201–209

    CAS  PubMed  Article  Google Scholar 

  16. Scholz J and Woolf CJ (2002) Can we conquer pain? Nat Neurosci 5 (Suppl): S1062–S1067

    Article  CAS  Google Scholar 

  17. Dubner R (1991) Neuronal plasticity in the spinal and medullary dorsal horns: a possible role in central pain mechanisms. In Pain and central nervous disease: the central pain syndromes, 143–155 (Ed Casey KL) New York: Raven Press

    Google Scholar 

  18. Hunt SP and Mantyh PW (2001) The molecular dynamics of pain control. Nat Rev Neurosci 2: 83–91

    CAS  PubMed  Article  Google Scholar 

  19. Hill R (2000) NK1 (substance P) receptor antagonists—why are they not analgesic in human? Trends Pharmacol Sci 21: 244–246

    CAS  PubMed  Article  Google Scholar 

  20. Goldstein DJ et al. (2001) Dose–response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy. Clin Neuropharmacol 24: 16–22

    CAS  PubMed  Article  Google Scholar 

  21. Sindrup SH et al. (2005) The NK1 receptor antagonist TKA731 in painful diabetic neuropathy. A randomised controlled trial. Eur J Pain [10.1016/j.ejpain.2005.08.001]

  22. Fields HL (1990) Pain syndromes in neurology, 286. London: Butterworths

    Google Scholar 

  23. Jensen TS et al. (2001) The clinical picture of neuropathic pain. Eur J Pharmacol 429: 1–11

    CAS  PubMed  Article  Google Scholar 

  24. Koltzenburg M (1998) Painful neuropathies. Curr Opin Neurol 11: 515–521

    CAS  PubMed  Article  Google Scholar 

  25. Hansson P et al. (2001) Aspects of clinical and experimental neuropathic pain: the clinical perspective. In Neuropathic pain: pathophysiology and treatment, progress in pain research and management, vol 21, 1–18 (Eds Hansson P et al.) Seattle: IASP Press

    Google Scholar 

  26. Woolf CJ and Max MB (2001) Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 95: 241–249

    CAS  PubMed  Article  Google Scholar 

  27. Jorum E et al. (2003) Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine—a double-blind, cross-over comparison with alfentanil and placebo. Pain 101: 229–235

    CAS  PubMed  Article  Google Scholar 

  28. Coderre TJ and Katz J (1997) Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. Behav Brain Sci 20: 404–419

    CAS  PubMed  Google Scholar 

  29. Woolf CJ (2004) Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 74: 2605–2610

    CAS  PubMed  Article  Google Scholar 

  30. Scholz J et al. (2005) Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 10: 7317–7323

    Article  CAS  Google Scholar 

  31. Le Bars D et al. (1992) Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter 1992 Jul–Aug: 55–65

  32. Porreca F et al. (2002) Chronic pain and medullary descending facilitation. Trends Neurosci 25: 319–325

    CAS  Article  PubMed  Google Scholar 

  33. Ren K and Dubner R (2002) Descending modulation in persistent pain: an update. Pain 100: 1–6

    PubMed  Article  Google Scholar 

  34. Hansson PT and Dickenson AH (2005) Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple etiologies. Pain 113: 251–254

    PubMed  Article  Google Scholar 

  35. Leung A et al. (2001) Concentration–effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 91: 177–187

    CAS  PubMed  Article  Google Scholar 

  36. Otto M et al. (2003) Pain phenomena and possible mechanisms in patients with painful polyneuropathy. Pain 101: 187–192

    PubMed  Article  Google Scholar 

  37. Max MB et al. (1987) Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 37: 589–596

    CAS  PubMed  Article  Google Scholar 

  38. Sindrup SH et al. (2003) Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology 60: 1284–1289

    CAS  PubMed  Article  Google Scholar 

  39. Fields HL et al. (1998) Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5: 209–227

    CAS  PubMed  Article  Google Scholar 

  40. Rowbotham MC et al. (1996) Cutaneous innervation density in the allodynic form of postherpetic neuralgia. Neurobiol Dis 3: 205–214

    CAS  PubMed  Article  Google Scholar 

  41. Rowbotham MC and Fields HL (1996) The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 119: 347–354

    PubMed  Article  Google Scholar 

  42. Petersen KL et al. (2000) Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 88: 125–133

    CAS  PubMed  Article  Google Scholar 

  43. Torebjork HE et al. (1992) Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 448: 765–780

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Gracely RH et al. (1992) Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51: 175–194

    CAS  PubMed  Article  Google Scholar 

  45. Koltzenburg M et al. (1992) Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 51: 207–219

    CAS  PubMed  Article  Google Scholar 

  46. Woolf CJ and Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288: 1765–1769

    CAS  PubMed  Article  Google Scholar 

  47. Nurmikko T and Bowsher D (1990) Somatosensory findings in postherpetic neuralgia. J Neurol Neurosurg Psychiatry 53: 135–141

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Baron R and Saguer M (1995) Mechanical allodynia in postherpetic neuralgia: evidence for central mechanisms depending on nociceptive C-fiber degeneration. Neurology 45 (Suppl 8): S63–S65

    CAS  PubMed  Article  Google Scholar 

  49. Loeser JD et al. (1968) Chronic deafferentation of human spinal cord neurons. J Neurosurg 29: 48–50

    CAS  PubMed  Article  Google Scholar 

  50. Nakata Y et al. (1979) Supersensitivity to substance P after dorsal root section. Life Sci 24: 1651–1654

    CAS  PubMed  Article  Google Scholar 

  51. Basbaum AI and Wall PD (1976) Chronic changes in the response of cells in adult cat dorsal horn following partial deafferentation: the appearance of responding cells in a previously non-responsive region. Brain Res 116: 181–204

    CAS  PubMed  Article  Google Scholar 

  52. Rowbotham MC and Fields HL (1989) Topical lidocaine reduces pain in post-herpetic neuralgia. Pain 38: 297–301

    CAS  PubMed  Article  Google Scholar 

  53. Attal N et al. (1999) Effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic neuralgia. Pain 81: 203–209

    CAS  PubMed  Article  Google Scholar 

  54. Rowbotham MC et al. (1995) Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 37: 246–253

    CAS  PubMed  Article  Google Scholar 

  55. Rowbotham MC et al. (1996) Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65: 39–44

    CAS  PubMed  Article  Google Scholar 

  56. Wasner G et al. (2005) Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin. J Neurol 252: 677–686

    CAS  PubMed  Article  Google Scholar 

  57. Herrmann DN et al. (2005) Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve [10.1002/mus.20419]

  58. Finnerup NB et al. (2002) Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain 96: 375–383

    CAS  PubMed  Article  Google Scholar 

  59. Attal N et al. (2004) Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 62: 218–225

    CAS  PubMed  Article  Google Scholar 

  60. Finnerup NB et al. (2005) Intravenous lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 102: 1023–1030

    CAS  PubMed  Article  Google Scholar 

  61. Wasner G et al. (2003) Complex regional pain syndrome—diagnostic, mechanisms, CNS involvement and therapy. Spinal Cord 41: 64–75

    Article  Google Scholar 

  62. Raja SN et al. (1991) Systemic alpha-adrenergic blockade with phenolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology 74: 691–698

    CAS  PubMed  Article  Google Scholar 

  63. Arner S (1991) Intraveneous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 46: 17–22

    CAS  PubMed  Article  Google Scholar 

  64. Rowbotham MC et al. (1991) Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 41: 1024–1028

    CAS  PubMed  Article  Google Scholar 

  65. Baranowski AP et al. (1999) A trial of intravenous lidocaine on the pain and allodynia of postherpetic neuralgia. J Pain Symptom Manage 17: 429–433

    CAS  PubMed  Article  Google Scholar 

  66. Attal N et al. (2000) Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology 54: 564–574

    CAS  PubMed  Article  Google Scholar 

  67. Wallace MS et al. (2000) Concentration–effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiology 92: 75–83

    CAS  PubMed  Article  Google Scholar 

  68. Meier T et al. (2003) Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106: 151–158

    CAS  PubMed  Article  Google Scholar 

  69. Wallace MS et al. (2000) Efficacy of oral mexiletine for neuropathic pain with allodynia: a double-blind, placebo-controlled, crossover study. Reg Anesth Pain Med 25: 459–467

    CAS  PubMed  Google Scholar 

  70. Vestergaard K et al. (2001) Lamotrigine for central poststroke pain: a randomized controlled trial. Neurology 56: 184–190

    CAS  PubMed  Article  Google Scholar 

  71. Eide PK et al. (1994) Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 58: 347–354

    CAS  PubMed  Article  Google Scholar 

  72. Eide PK et al. (1995) Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation. Neurosurgery 37: 1080–1087

    CAS  PubMed  Article  Google Scholar 

  73. Felsby S et al. (1996) NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain 64: 283–291

    CAS  PubMed  Article  Google Scholar 

  74. Max MB et al. (1995) Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 18: 360–368

    CAS  PubMed  Article  Google Scholar 

  75. Attal N et al. (2002) Effects of IV morphine in central pain: a randomized placebo-controlled study. Neurology 58: 554–563

    CAS  PubMed  Article  Google Scholar 

  76. Watson CP and Babul N (1998) Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 50: 1837–1841

    CAS  PubMed  Article  Google Scholar 

  77. Watson CP et al. (2003) Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 105: 71–78

    CAS  PubMed  Article  Google Scholar 

  78. Sindrup SH et al. (1999) The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels. Clin Pharmacol Ther 66: 636–641

    CAS  PubMed  Article  Google Scholar 

  79. Canavero S and Bonicalzi V (2004) Intravenous subhypnotic propofol in central pain: a double-blind, placebo-controlled, crossover study. Clin Neuropharmacol 27: 182–186

    CAS  PubMed  Article  Google Scholar 

  80. Yucel A et al. (2005) The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Eur J Pain 9: 407–416

    CAS  PubMed  Article  Google Scholar 

  81. McAdoo DJ et al. (1999) Changes in amino acid concentrations over time and space around an impact injury and their diffusion through the rat spinal cord. Exp Neurol 159: 538–544

    CAS  PubMed  Article  Google Scholar 

  82. Gwak YS and Hulsebosch CE (2005) Upregulation of Group I metabotropic glutamate receptors in neurons and astrocytes in the dorsal horn following spinal cord injury. Exp Neurol 195: 236–243

    CAS  PubMed  Article  Google Scholar 

  83. Liu J et al. (2004) Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. Mol Ther 10: 57–66

    CAS  PubMed  Article  Google Scholar 

  84. Hains BC et al. (2003) Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23: 8881–8892

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Correspondence to Nanna B Finnerup.

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Finnerup, N., Jensen, T. Mechanisms of Disease: mechanism-based classification of neuropathic pain—a critical analysis. Nat Rev Neurol 2, 107–115 (2006). https://doi.org/10.1038/ncpneuro0118

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